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Abstract
Antimicrobial chemotherapy has conferred huge benefits on human health. A variety of microorganisms were
elucidated to cause infectious diseases in the latter half of the 19th century. Thereafter, antimicrobial chemo-
therapy made remarkable advances during the 20th century, resulting in the overly optimistic view that infectious
diseases would be conquered in the near future. However, in response to the development of antimicrobial
agents, microorganisms that have acquired resistance to drugs through a variety of mechanisms have emerged
and continue to plague human beings. In Japan, as in other countries, infectious diseases caused by drug-
resistant bacteria are one of the most important problems in daily clinical practice. In the current situation, where
multidrug-resistant bacteria have spread widely, options for treatment with antimicrobial agents are limited, and
the number of brand new drugs placed on the market is decreasing. Since drug-resistant bacteria have been
selected by the use of antimicrobial drugs, the proper use of currently available antimicrobial drugs, as well as
efforts to minimize the transmission and spread of resistant bacteria through appropriate infection control, would
be the first step in resolving the issue of resistant organisms.
*1 Assistant Professor, Department of Microbiology and Infectious Disease, Faculty of Medicine, Toho University, Tokyo, Japan
(sagatomoo@med.toho-u.ac.jp).
*2 Professor, Department of Microbiology and Infectious Disease, Faculty of Medicine, Toho University, Tokyo, Japan.
This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol.137, No.3, 2008,
pages 513–517).
Discovery of penicillin
Discovery of a sulfonamide
Clinical application of penicillin
Emergence of penicillinase-producing
Staphylococcus aureus Discovery of aminoglycoside, chloramphenicol,
tetracycline, and macrolide
Emergence and spread of multidrug-resistant
S. aureus Discovery of vancomycin
Synthesis of methicillin
Emergence of MRSA
Synthesis of nalidixic acid
Emergence of PISP Development of first-generation cephems
Emergence of penicillinase-producing
H. influenzae Development of second-generation cephems
Emergence of PRSP
Emergence of BLNAR H. influenzae Development of third-generation cephems
Emergence of ESBL-producing Gram-negative
Development of carbapenem Development of
bacilli
and monobactam new quinolones
Emergence of VRE
Increased infections with MRSA, PRSP, BLNAR,
etc. Increased use of third-generation
Increase of resistant gonococci cephem, carbapenem, oral cephem, and
new quinolone antimicrobials
Increase of MDRP
Increase of quinolone-resistant E. coli (Decrease in newly developed antimicrobial agents)
Nalidixic acid
Penicillin G
Ampicillin
Norfloxacin
Methicillin
Levofloxacin
Piperacillin
agents continued to achieve a broader antimicro- microbial spectra. First-generation cephems (cefaz-
bial spectrum and higher antimicrobial activity. - olin, etc.) are effective only for Gram-positive
lactam antibiotics will be described as an example. organisms and Escherichia coli, although their
The -lactam antibiotics include penicillins (Fig. 2), antimicrobial activity against these organisms is
cephems, carbapenems, and monobactams. potent. Second-generation cephems (cefotiam,
Penicillins were originally effective for Gram- etc.) have an extended antimicrobial spectrum
positive organisms such as S. aureus. Later, to that covers not only Gram-positive but also Gram-
address penicillin-resistant S. aureus which pro- negative organisms including other Enterobacte-
duces the penicillin-hydrolysing enzyme penicil- riaceae. Third-generation cephems (ceftazidime,
linase, methicillin was developed. On the other cefotaxime, etc.) have higher efficacy for Gram-
hand, attempts to expand the antimicrobial spec- negative organisms, and some drugs of this
trum yielded ampicillin, which is also effective for generation are also effective for P. aeruginosa,
Gram-negative Enterobacteriaceae, and piper- although the antimicrobial activity against Gram-
acillin, which is effective even for Pseudomonas positive organisms is generally lower than that of
aeruginosa. the first generation.
Cephems were developed in the 1960s, and Carbapenem is an antibiotic class including
came into widespread use. Cephems are classified panipenem, imipenem, and meropenem. These
into several generations according to their anti- drugs are effective not only for Gram-positive
and Gram-negative bacteria but also anaerobes, was metabolized rapidly in the human body.
and their antimicrobial activity is strong. The In contrast, norfloxacin, which came to market
monobactam antibiotic aztreonam exerts an anti- in 1984, maintains a stable metabolic state and
microbial effect only on Gram-negative bacteria. exhibits good tissue distribution. Its antimicro-
Continuing improvements have been made for bial spectrum is extensive, covering both Gram-
antimicrobial agents in various aspects in addi- positive and Gram-negative bacteria including
tion to the antimicrobial spectrum and activity. P. aeruginosa. Quinolone antimicrobials developed
The drugs have been developed to achieve better after norfloxacin have been called new quinolones,
pharmacodynamics including the absorption of and they have still been key drugs. Levofloxacin
oral drugs, concentration in the blood, and distri- is the S-(ⳮ) enantiomer of the new quinolone
bution to the inflammatory focus. In addition, as ofloxacin. This enantiomer has higher antimicro-
antimicrobial chemotherapy has been established bial activity than that of the other R-(Ⳮ) enanti-
and matured, more importance has been attached omer of ofloxacin, and is associated with weaker
to the drug safety. Antimicrobial agents that are side effects on the central nervous system, such as
associated with serious side effects have been restlessness and vertigo.
replaced by other safer drugs. Although a large number of companies in
Quinolone antimicrobials represent an example various countries have competed in the develop-
of drugs with improved pharmacodynamics and ment of newer antimicrobial agents, the number
safety (Fig. 2). Nalidixic acid, the first drug of of brand new drugs has been remarkably decreas-
this class, was active only against Gram-negative ing in recent years, with few antimicrobial agents
bacteria, and its use was limited to urinary tract of new classes becoming available. In contrast,
infections because it achieves only low blood infectious diseases continue to attack human
concentrations and poor tissue distribution, and beings as emerging and re-emerging infectious
diseases, opportunistic infectious diseases, and thickening of the cell wall contributes to decreased
infection with drug-resistant microorganisms sensitivity to this drug. On the other hand,
that will be discussed in the next section. Effec- vancomycin-resistant S. aureus (VRSA) reported
tive utilization of the current limited options is in the US seemed to acquire the resistance
much more important under the dearth of new genes horizontally from vancomycin-resistant
drugs on the market. enterococci (VRE).5 In Japan, there have been
no reports of VRSA strains so far, partially at
History of the Emergence of Resistant least, due to lower detection rates of VRE than
Bacteria those in Western countries.
Although S. pneumoniae was originally sus-
The capacity of microorganisms to acquire resis- ceptible to penicillin, penicillin-intermediate S.
tance to antimicrobial agents has surpassed our pneumoniae (PISP) strains were found in the
imagination. In some cases, antimicrobial agents latter half of the 1960s, and penicillin-resistant
formerly effective are no longer useful. The history S. pneumoniae (PRSP) strains in the latter half
of resistant bacteria will be outlined below and of the 1970s. In Japan, PRSP was found in the
in Table 1. 1980s, and the detection of PRSP strains began
S. aureus is the resistant bacterium most familiar to increase around 1990. Frequent use of oral
in the clinical setting. This bacterium rapidly cephem antibiotics seems to be responsible for
acquired resistance to sulfonamides when they this increase in PRSP. There has also been a
were in use. Penicillin was initially effective remarkable increase in macrolide resistance in
to this microorganism, but resistant strains that this species, which seems also due to the frequent
produce penicillinase increased in the 1950s. use of macrolides in this country.
Therefore, penicillinase-stable methicillin was Ampicillin was initially effective for Haemoph-
developed in 1960, as mentioned previously. ilus influenzae. However, in the 1980s, some of
However, as early as the following year, 1961, this species were found to produce -lactamase,
methicillin-resistant S. aureus (MRSA) was iso- thereby becoming resistant to ampicillin. In
lated in the UK.3 the 1990s, such -lactamase-producing strains
Since around 1990, nosocomial infection with decreased in Japan, however, strains that acquired
MRSA became a social problem. During this highly resistance to -lactam through mutations
period, the target of new antimicrobial agents in PBP genes, increased instead. These are
including second- and third-generation cephems, called as -lactamase-negative ampicillin-resistant
shifted from Gram-positive to Gram-negative (BLNAR) strains, and they are more common
bacteria, and agents with wide spectra but in Japan than in other Western countries. It
weaker activity against Gram-positive bacteria has been speculated that increased use of oral
were widely used (Fig. 1). MRSA acquires resis- cephem antibiotics is also responsible, similar to
tance to most -lactam antibiotics through its the situation with PRSP.
acquisition of the penicillin-binding protein (PBP) Although P. aeruginosa are intrinsically resis-
2’ gene; PBP2’ is an enzyme involved in cell tant to many antimicrobial agents, the emergence
wall synthesis that has low binding affinity for of P. aeruginosa strains resistant to all of three
-lactam antibiotics. In genetic lineage analysis classes of antimicrobials, i.e., carbapenems, quino-
of nosocomial MRSA strains, major nosocomial lones, and aminoglycosides is a recent concern.
clones throughout the world would converge on These multidrug resistant P. aeruginosa (MDRP)
only seven types.4 On the other hand, community- sometimes seems to cause an outbreak in some
associated methicillin-resistant S. aureus (CA- institutions. MDRP has complex mechanisms of
MRSA), which was noticed in the US around drug resistance, including reduced membrane
1997, is of a different type from nosocomial permeability due to decreased outer membrane
MRSA. protein (D2 porin), overexpression of efflux
Fortunately, MRSA so far in Japan have pump, mutation of the quinolone target (DNA
responded to glycopeptide antibiotics such as gyrase), production of aminoglycoside modifi-
vancomycin. However, in the latter half of the cation enzyme, and production of metallo--
1990s, vancomycin-intermediate S. aureus (VISA) lactamase (carbapenem-hydrolysing enzyme).
was reported in this country. It is thought that Some resistance genes are horizontally trans-
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